Allo: Hodgkin's

Overview

A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the role that allogeneic stem cell plays in the treatment of Hodgkin's disease. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials. For a general overview of the process of allogeneic stem cell transplant, select Allogeneic Stem Cell Transplant.

Comparison of Allogeneic to Autologous Stem Cell Transplantation

Standard initial treatment of recurrent Hodgkin’s disease is currently autologous stem cell transplantation because this treatment approach cures over 50% of patients with recurrent disease, with less than 5% of patients dying from complications of therapy.

The role of allogeneic stem cell transplantation in the management of Hodgkin’s disease is limited to patients with resistant or refractory cancer, or patients who are unable to undergo an autologous stem cell transplant, usually because of the inability to collect sufficient stem cells to support the procedure. Allogeneic stem cell transplantation, in general, is associated with greater side effects, resulting in more treatment related deaths than treatment with autologous stem cell transplantation. Patients treated with allogeneic stem cell transplantation, however, are less likely to develop a cancer recurrence. This is because of the immunologic effect that the allogeneic transplant has on eradicating cancer cells remaining in the patient. Because allogeneic stem cell transplantation is associated with greater side effects but appears more capable of preventing cancer recurrences, its use is largely limited to patients with resistant or refractory disease that have failed multiple other treatments.

In order to better advise patients about the relative benefits of autologous and allogeneic stem cell transplantation, doctors have tried to evaluate and compare these therapies. In one clinical study, researchers compared the outcomes of 45 patients with Hodgkin’s disease who received an allogeneic stem cell transplant to the outcomes of 45 similar patients who received an autologous transplant. All patients had failed primary and often secondary treatments. Twenty-five percent of patients who received an allogeneic transplant survived 4 years after treatment, compared to 48% of patients who received an autologous stem cell transplant. Death from side effects occurred in 48% of patients who received an allogeneic stem cell transplant, compared to 27% of patients who received an autologous transplant.

In another clinical study, the outcomes of 127 patients with Hodgkin’s disease receiving allogeneic or autologous transplants were compared. All patients had failed at least one and usually multiple treatments. Almost half of the patients died of treatment related causes. Recipients of allogeneic bone marrow transplants had a lower recurrence rate but a higher death rate from side effects. There were no differences in survival between recipients of allogeneic or autologous transplants, with approximately 20% of patients surviving 5 years from treatment.

These studies were carried out before 1995 and there has been significant progress in decreasing the treatment related deaths following both an allogeneic or autologous stem cell transplant. Allogeneic stem cell transplants in patients under the age of 60 are currently associated with a treatment related mortality of 20-40% and autologous transplants have a treatment related mortality under 5%. Although comparative studies have not been recently performed, it is safe to conclude that the majority of patients who fail initial chemotherapy and have sufficient stem cells should receive an autologous transplant rather than an allogeneic transplant. However, patients with refractory disease or insufficient stem cells to support autologous transplantation should consider an allogeneic stem cell transplant. For younger patients with aggressive Hodgkin's lymphoma, allogeneic stem cell transplantation may also be a reasonable treatment option.

Researchers at John Hopkins Oncology Center recently analyzed treatment and outcomes of 157 patients with recurrent Hodgkin’s lymphoma who underwent a stem cell transplant between March 1985 and April 1998. Fifty-three patients were treated with an allogeneic stem cell transplant and 104 were treated with an autologous stem cell transplant. Ten years following therapy, the chance of a relapse for patients treated with an allogeneic transplant was 53%, compared to 60% for patients treated with an autologous transplant. Among patients still responsive to standard chemotherapy, allogeneic stem cell transplants produced far fewer relapses than autologous stem cell transplants (34% versus 51%). Importantly, for 2 years following treatment with an autologous stem cell transplant, there was a continued risk of a relapse and of developing acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) caused by the treatment. In contrast, there were no cases of secondary AML/MDS or relapses beyond three years after an allogeneic stem cell transplant. This long-term clinical study suggests that patients with recurrent Hodgkin’s treated with an allogeneic stem cell transplant experience fewer relapses and fewer incidences of treatment-induced AML/MDS when compared to patients treated with autologous stem cell transplants.

Strategies to Improve Treatment

The main reasons patients with Hodgkin's disease fail treatment with an allogeneic transplant are cancer relapse and death from side effects of treatment. Relapse of Hodgkin's disease occurs because the high-dose treatment is unable to kill all of the cancer cells. Treatment-related deaths are due to chemotherapy related side effects, infections and graft-versus-host disease. Allogeneic stem cell transplants are also limited by donor availability, since only about one-third of patients will have an HLA-compatible family member donor. Doctors are performing clinical trials designed to improve the treatment of patients with Hodgkin's disease by the following approaches:

Use of Peripheral Blood Stem Cells: Stem cells may be collected from a number of sites in the body, including the bone marrow and the peripheral blood. Physicians at The Fred Hutchinson Cancer Center, City of Hope, and Stanford University performed a randomized clinical trial comparing allogeneic bone marrow transplantation (BMT) to peripheral blood stem cell (PBSC) transplantation in patients with leukemia and lymphoma. The results of this study were presented at the American Society of Hematology Annual Meeting in New Orleans.

Patients receiving PBSC experienced more rapid recovery from treatment than patients receiving BMT. White blood cell counts recovered 5 days earlier and platelets recovered 8 days earlier. There were more deaths in patients receiving bone marrow due to lung complications, infections and cancer recurrence. This occurred predominantly in patients with more advanced cancers. There was no difference in the incidence of acute graft-versus-host disease and there was an increase in the incidence of chronic graft-versus-host disease of approximately 10% in patients receiving PBSC. Although, the follow-up period for this study is too short to make definite conclusions about the incidence and severity of chronic graft versus host disease, the physicians concluded that allogeneic peripheral blood stem cells were superior to bone marrow stem cells.

Enhancement of Immunity after Stem Cell Transplants: Allogeneic stem cell transplants are more effective in preventing relapses than autologous transplants because the donor cells recognize the cancer as foreign and kill cancer cells immunologically. Despite this graft-versus-lymphoma reaction, many patients still relapse. Clinical trials are ongoing to evaluate strategies to enhance this graft-versus-lymphoma effect.

Biological Modifier Therapy: Biologic response modifiers are naturally occurring or synthesized substances that direct, facilitate, or enhance the body's normal immune defenses. Biologic response modifiers include interferons, interleukins, and monoclonal antibodies. In an attempt to improve survival rates, these and other agents are being evaluated following treatment with an allogeneic stem cell transplant.

Donor White Blood Cell Infusions: In patients who do not have graft-versus-host disease following an allogeneic stem cell transplant, further infusions of white blood cells from the donor are being evaluated to prevent or treat relapses after the transplant. In some studies, these cells are combined with a biologic response modifier, such as interleukin-2, to further enhance the graft-versus-leukemia reaction.

Lymphocytes are white blood cells that are part of the body’s immune system and are capable of destroying cancer cells. Doctors have been trying for several years to use lymphocytes (a type of white blood cell) reactive specifically against cancer cells as a form of treatment. For many reasons, this has been a difficult goal to achieve. First, billions of lymphocytes are needed in order to have a therapeutic effect because it takes several lymphocytes to kill a single cancer cell. Thus, in order for lymphocyte infusions to be practical therapy, extremely large numbers of specific immune lymphocytes need to be produced. Getting lymphocytes to grow and multiply in culture systems outside the body has been difficult. Second, the lymphocytes grown in culture have to be specifically reactive to the cancer cell that has to be killed. Lymphocytes normally attack and kill a variety of foreign invaders, but each lymphocyte is specific and only kills one target and no other. Third, the immune lymphocytes must survive and not be destroyed when infused into a patient with cancer.

Recently, doctors in Holland have been able to grow and expand lymphocytes outside the body that kill leukemia cells without damaging normal cells. When they infused these lymphocytes into a patient with leukemia, the patient achieved a complete disappearance of leukemia. This may represent the first time expanded T lymphocytes have been shown to have a beneficial anti-cancer effect when infused into a patient.

Unfortunately, the use of donor lymphocytes can also be associated with the development of graft-versus-host disease. Several recent studies suggest that the risk for developing graft-versus-host disease may be decreased if a specific type of lymphocyte, the CD8 lymphocyte, is removed. Until now, there has not been an effective and efficient way to remove, or deplete, these CD8 cells from the other donor lymphocytes. Just recently, European researchers presenting at the European Group for Blood and Marrow Transplantation meeting in Austria reported the use of a new technique to deplete the CD8 lymphocytes from the donor cells that are to be infused into the patient.

Researchers treated 9 patients who experienced a recurrence of leukemia after undergoing high-dose therapy and an allogeneic stem cell transplantation. The researchers collected lymphocytes from the respective donors. They were able to deplete 98 to 100% of the CD8 lymphocytes from the donor lymphocyte samples, while still retaining 75% of the other lymphocytes needed to treat the recurrent leukemia. The donor CD8-depleted lymphocytes were then infused into the corresponding patients. Only 1 of the 9 patients developed graft-versus-host disease, a number much lower than would usually occur if CD8 lymphocytes were not depleted from the infusion.

These researchers concluded that the depletion of CD8 lymphocytes from the other donor lymphocytes by high-density microsphere separation appears to be effective. Furthermore, the CD8-depleted donor lymphocyte infusion appeared to decrease the incidence of graft-versus-host disease, while preserving the therapy’s anti-leukemia effect.

Graft Manipulation: For many years, it has been known that the removal of lymphocytes from the graft (donor stem cells) could prevent or ameliorate the graft-versus-host reaction. However, when T-cells are removed from the graft, there is an increase in graft failure and relapse rates. Many clinical trials are currently being carried out to determine the optimal cellular composition of the graft to ensure engraftment, without graft-versus-host disease and without an increase in relapse. These studies have been made easier by the development of blood stem cell transplants, which allow for the collection and processing of large numbers of donor stem cells from peripheral blood.

Increase in the use of Donors other than HLA-Matched Siblings: Since less than a quarter of patients will have an HLA-matched family member donor, there is much ongoing research into increasing the donor pool. There has been significant progress in the use of partially matched family member donors, especially in children. At the present time, an HLA-compatible unrelated donor can be found for approximately 70% of patients; however, the search must be initiated early enough in the disease course to be of benefit. There is also increasing definition of the degree of mismatching that can be tolerated in unrelated donors, especially in children. The use of umbilical cord blood is expanding and will increase the unrelated donor pool. Umbilical cord blood transplants have until recently been restricted to small children due to the low volume of stem cells present in cord blood. Recent clinical studies suggest that the cells collected from cord blood can be expanded in culture and used successfully in older, heavier children and in adults.

"Mini-transplants": The high-dose radiation and chemotherapy regimens used in allogeneic stem cell transplants are very toxic and involve complete destruction of the bone marrow. Recently, several transplant centers have evaluated less toxic regimens, including lower doses of chemotherapy, radiation and/or biologic therapy prior to an allogeneic transplant. The concept of a mini-transplant is two-fold. The less toxic regimens utilizing lower doses of chemotherapy, radiation therapy and/or biologic therapy kill some cancer cells and suppress the patient’s immune system so that it won’t attack the donor cells. Once the donor cells are infused into the patient, they can recognize the patient’s cancer cells as foreign and mount an attack against the cancer.

Several small clinical trials have demonstrated that successful eradication of leukemia cells can be achieved with ("mini-transplants"). This represents a potential new approach for safer treatment of a large variety of cancers currently treated with allogeneic stem cell transplantation, including Hodgkin’s disease. The technique of mini-transplants has now been expanded to include the use of unrelated HLA-matched donors and has the potential to make this therapy more widely applicable.

Increased Dose Intensity: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered to the lymphoma cells by utilizing high doses of anti-cancer therapies is one strategy to improve cure rates. The strategy of increasing the dose of chemotherapy and total body irradiation however is applicable only to children as toxicities of this approach are too high in adults.